Tgf-Beta Enhances The Laminin-1-Induced Production Of Il-16 In Ra Synovial Fibroblasts By Elevation Of Beta1-Integrin Expression

Objectives Synovial tissue of rheumatoid arthritis (RA) patients is characterized by strong expression of laminins and release of inflammatory cytokines, one of which is IL‐16. In this study we investigated regulatory pathways of IL‐16 in synovial fibroblasts (SF) from RA and osteoarthritis (OA) patients. Methods We analyzed attachment to LM‐111 and expression of integrins in SF. Expression of IL‐16 in SF grown on LM‐111 w/o TGF‐beta was quantified by qRT‐PCR and ELISA. Activity of IL‐16 was monitored in a cell migration assay. TGF‐induced signaling pathways were studied by immunoblotting and by blocking with p38MAPK‐, MEK‐, and Smad2 inhibitors. Results TGF‐activated SF showed an upregulation of beta1‐integrin and adhered more closely to LM‐111. This attachment to LM‐111 could be blocked by mAb to beta1‐integrin. Stimulation with TGF and growth on LM‐111 significantly increased IL‐16 mRNA and protein in RA‐SF. In OA‐SF, TGF failed to induce production of IL‐16. Expression of IL‐16 was regulated by p38MAPK, MEK‐ERK1/2 and Smad2 signaling. Conclusion The adherence of RA‐SF to LM‐111 in the presence of TGF triggers a significant IL‐16 response and thus contributes to the infiltration of CD4+ lymphocytes into synovial tissues. This mode of induction of IL‐16 represents a novel pathway that results in IL‐16 production in RA‐SF but not in OA‐SF.